Regulation of Renal Progenitor Cells in Regenerating Kidneys

 描述（由申请人提供）：肾脏具有在损伤后再生的固有能力。这种修复伴随着转录因子基因如Pax 2和Lhx 1的表达，这些基因是启动正常肾器官形成所必需的，这表明再生的肾小管细胞来自具有原始的祖细胞样状态的细胞。肾祖细胞可以在肾小管上皮细胞的“重编程”后形成，如在哺乳动物中，或从永久驻留在肾中的细胞形成，例如成年斑马鱼。我们假设任何扩大或增强肾祖细胞的治疗都将加速急性肾损伤（阿基）后的恢复速度。为了测试这一点，我们在斑马鱼中开发了阿基的幼体和成体模型，并开发了独特的工具和方法来操纵肾祖细胞。我们进行了高含量筛选，以确定增加肾祖细胞数量的化合物，并确定了一类新的组蛋白脱乙酰酶抑制剂（HDACis），PTBA，当在诱导损伤后给予时，可加速斑马鱼和阿基小鼠模型的肾恢复。拟议的修订将侧重于PTBA类化合物的作用机制，并分为三个子目标，利用两个不同机构研究人员的互补专业知识。子目标1：我们将测试PTBA治疗是否驱动阿基模型中的G2/M期逃逸与S期阻滞。子目标2：我们将鉴定PTBA处理的PTEC的转录靶点。子目标3：我们将对促进G2/M检查点逃逸的候选人进行功能分析。

 DESCRIPTION (provided by applicant): The kidney has an inherent ability to regenerate following damage. This repair is concomitant with the expression of transcription factor genes such as Pax2 and Lhx1, which are essential for initiating normal kidney organogenesis, suggesting that regenerating tubular cells arise from cells with a primitive, progenitor-like state Renal progenitors may be formed following the "re-programming" of tubular epithelial cells, such as in mammals, or from cells that permanently reside in the kidney, such as in the adult zebrafish. We hypothesize that any treatment that expands or enhances renal progenitors will accelerate the rate of recovery following acute kidney injury (AKI). To test this we developed larval and adult models of AKI in zebrafish and developed unique tools and methodologies to manipulate renal progenitors. We performed a high-content screen to identify compounds that enhance renal progenitor cell number and identified a novel class of histone deacetylase inhibitors (HDACis), the PTBAs, that accelerates renal recovery in zebrafish and mouse models of AKI when given after the induction of injury. The proposed revision will focus on the mechanism of action for PTBA class compounds and is divided into three sub-aims, which take advantage of the complementary expertise of investigators at two different institutions. Sub-Aim 1: We will test if PTBA treatment drives G2/M escape vs. S phase arrest in AKI models. Sub-Aim 2: We will identify transcriptional targets of PTBA treated PTECs. Sub-Aim 3: We will perform functional analysis of candidates that promote G2/M checkpoint escape.